This proposal outlines an integrative five-year training program for the candidate, Arnold Han, M.D., Ph.D., in his development as an independent physician-scientist. Dr. Han is clinically trained as a gastroenterologist and has a Ph.D. in immunology. He is doing postdoctoral research under the mentorship of Dr. Mark Davis, Professor of Microbiology and Immunology at Stanford University and Investigator with the Howard Hughes Medical Institute. In his proposal entitled The intraepithelial T cell response in celiac disease, Dr. Han aims to better understand celiac disease (CD), an incurable autoimmune disease that affects millions of Americans, and many more worldwide. The research further investigates the observation that intraepithelial T lymphocytes (T-IEL) in CD are deliberately recruited to the intestine in response to gluten. T-IELs are the cells held responsibl for the detrimental consequences of CD, including intestinal damage and lymphoma development. As a follow up, the proposal aims to better understand mechanisms through with T-IEL are activated and recruited to the intestine in CD. The research explores the hypothesis that gluten-specific CD4+ T cell responses enable T-IEL responses directed against antigens other than gluten. The proposed research investigates the nature and mechanisms of T-IEL responses in CD through the following aims: 1) Examine the mechanisms through which gluten enables ?? T cell activation in celiac disease through the study of ?? T cell function in peripheral blood and tissue. 2) Examine the mechanisms through which gluten enables tissue damage by CD8+ T cells in CD. 3) Analyze mechanisms through which T-IELs are activated and recruited to the intestinal epithelium through the study of antigen-specific T-IEL responses in humanized mouse models. These aims leverage Dr. Han's clinical training in gastroenterology, his post-doctoral research training in the study of human mucosal T cells, and the expertise of the Mark Davis laboratory and collaborators. Successful completion of these aims may ultimately enable the development of novel approaches in the prevention and treatment of CD and other autoimmune diseases. Concurrently, Dr. Han will complete a structured career development-training program, overseen by mentors within the Division of Gastroenterology and Hepatology and other faculty at the Stanford University School of Medicine. This plan will include didactic, clinical, and managerial experience necessary to achieve Dr. Han's ultimate goal of becoming a successful, independent physician-scientist.